(Biomarker)
When biological information is converted into a numerical value and quantified as an index for quantitatively comprehending biological changes in a living body, it is called a “biomarker.”
According to FDA (United States Food and Drug Administration), a biomarker is regarded as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention.” Biomarkers representative of state of disease, changes or degree of healing are used as surrogate markers (substitute markers) to monitor efficacy in clinical tests of new drugs. Blood sugar level and cholesterol level are representative biomarkers used as indexes of lifestyle diseases. Biomarkers include not only substances of biological origin contained in urine or blood but also electrocardiogram, blood pressure, PET images, bone density, lung function and the like. Developments in genomic analysis and proteome analysis have lead to discovery of various biomarkers related to DNA, RNA or biological protein.
Biomarkers are promising for measuring therapeutic efficacy after the onset of a disease and, in addition, as routine preventive indexes, promising for disease prevention. Further, application of biomarkers to individualized medicine for selecting effective treatment avoiding side effects is expected.
In the field of neurological/mental disorder, however, though studies directed to molecular markers and the like usable as objective indexes from a biochemical or molecular genetics viewpoint have been made, it will be justified to say that they are still under consideration.
Meanwhile, a disease determination system using NIRS (Near-InfraRed Spectroscopy), classifying mental disorders such as schizophrenia and depression based on features of hemoglobin signals measured by biological optical measurement, is reported (Non-Patent Literature 1).
(Real Time Neurofeedback)
Conventionally, as therapies for Obsessive-Compulsive Disorder (OCD) as one type of neurotic disease, for example, pharmacological and behavioral treatments have been known. The pharmacological treatment uses, for example, serotonin-selective reuptake inhibitor. As the behavioral treatment, exposure response prevention therapy, combining exposure therapy and response prevention has been known.
Meanwhile, real time neurofeedback is studied as a possible therapy for neurological/mental disorder.
Functional brain imaging, including functional Magnetic Resonance Imaging (fMRI), which visualizes hemodynamic reaction related to human brain activities using Magnetic Resonance Imaging (MRI), has been used to specify an active region of a brain corresponding to a component of brain function of interest, that is, to clarify functional localization of brain, by detecting difference between those in brain activities while responding to a sensory stimulus or performing a cognitive task, and those brain activities in a resting state or while performing a control task.
Recently, real time neurofeedback technique using functional brain imaging such as functional magnetic response imaging (fMRI) is reported (Non-Patent Literature 1). Real time neurofeedback technique has come to attract attention as a possible therapy of neurological disorder and mental disorder.
Neurofeedback is one type of bio-feedback, in which a subject receives feedback about his/her brain activities and thereby learns a method of managing brain activities.
By way of example, according to a report, activities of anterior cingulate cortex are measured by fMRI, the measurements are fed back to patients on real time basis as larger or smaller fire image, and the patients are instructed to make efforts to decrease the size of the fire, then improvement was attained both in real-time and long-term chronic pain of central origin (see Non-Patent Literature 2).
(Resting State fMRI)
Further, recent studies show that even when a subject is in the resting state, his/her brain works actively. Specifically, in the brain, there is a group of nerve cells that subside when the brain works actively and are excited vigorously in the resting state. Anatomically, these cells mainly exist on the medial surface where left and right cerebral hemispheres are connected such as medial aspect of the frontal lobe, posterior cingulate cortex, precuneus, posterior portion of parietal association area and middle temporal gyrus. The regions representing baseline brain activity in the resting state are named Default Mode Network (DMN) and these regions work in synchronization as one network (see Non-Patent Literature 3).
An example of difference between brain activities of a healthy individual and those of a patient of mental disease is observed in brain activities in the default mode network. The default mode network refers to portions of one's brain that exhibit more positive brain activities when a subject is in the resting state than when the subject is performing a goal-directed task. It has been reported that abnormality is observed in the default mode network of patients of mental disorder such as schizophrenia or Alzheimer's disease as compared with healthy individuals. By way of example, it is reported that in the brain of a schizophrenia patient, correlation of activities among posterior cingulate cortex, which belongs to the default mode network, and parietal lateral cortex, medial prefrontal cortex or cerebellar cortex, is decreased in the resting state.
At present, however, it is not necessarily clear how the default mode network as such relates to the cognitive function and how the correlations of functional connectivity among brain regions relates to the above-described neurofeedback.
On the other hand, changes in correlations between activities among a plurality of brain regions caused, for example, by difference in tasks are observed, so as to evaluate functional connectivity between these brain regions. Specifically, evaluation of functional connectivity in the resting state obtained by fMRI is referred to as resting-state functional connectivity MRI (rs-fcMRI), which is utilized for clinical studies directed to various neurological/mental disorders. The conventional rs-fcMRI, however, is for observing activities of global neural network such as the default mode network described above, and more detailed functional connectivity is not yet sufficiently considered.
(DecNef Method: Decoded NeuroFeedback)
On the other hand, a new type neural feedback method referred to as decoded neurofeedback (DecNef) is reported recently (see Non-Patent Literature 4).
Human sensory and esthesic systems are ever-changing in accordance with the surrounding environment. Most of the changes occur in a certain early period of human developmental stage, or the period referred to as a “critical period.” Adults, however, still keep sufficient degree of plasticity of sensory and esthesic systems to adapt to significant changes in surrounding environment. By way of example, it is reported that adults subjected to a training using specific esthesic stimulus or exposed to specific esthesic stimulus have improved performance for the training task or improved sensitivity to the esthesic stimulus, and that such results of training were maintained for a few months to a few years (see Non-Patent Literature 5). Such a change is referred to as sensory learning, and it has been confirmed that such a change occurs in every sensory organ, that is, vision, audition, olfaction, gustation, and taction.
According to DecNef, a stimulus as an object of learning is not directly applied to a subject while brain activities are detected and decoded, and only the degree of approximation to a desired brain activity is fed back to the subject to enable “sensory learning.”
(Nuclear Magnetic Resonance Imaging)
Nuclear Magnetic Resonance Imaging will be briefly described in the following.
Conventionally, as a method of imaging cross-sections of the brain or the whole body of a living body, nuclear magnetic resonance imaging has been used, for example, for human clinical diagnostic imaging, which method utilizes nuclear magnetic resonance with atoms in the living body, particularly with atomic nuclei of hydrogen atoms.
As compared with “X-ray CT,” which is a similar method of human tomographic imaging, characteristics of nuclear magnetic resonance imaging when applied to a human body, for example, are as follows:
(1) An image density distribution reflecting distribution of hydrogen atoms and their signal relaxation time (reflecting strength of atomic bonding) are obtained. Therefore, the shadings present different nature of tissues, making it easier to observe difference in tissues;
(2) The magnetic field is not absorbed by bones. Therefore, a portion surrounded by a bone or bones (for example, inside one's skull, or spinal cord) can easily be observed; and
(3) Unlike X-ray, it is not harmful to human body and, hence, it has a wide range of possible applications.
Nuclear magnetic resonance imaging described above uses magnetic property of hydrogen atomic nuclei (protons), which are most abundant in human cells and have highest magnetism. Motion in a magnetic field of spin angular momentum associated with the magnetism of hydrogen atomic nucleus is, classically, compared to precession of spin of a spinning top.
In the following, as a description of background of the present invention, the principle of magnetic resonance will be summarized using the intuitive classical model.
The direction of spin angular momentum of hydrogen atomic nucleus (direction of axis of rotation of spinning top) is random in an environment free of magnetic field. When a static magnetic field is applied, however, the momentum is aligned with the line of magnetic force.
In this state, when an oscillating magnetic field is superposed and the frequency of oscillating magnetic field is resonance frequency f0=γB0/2π (γ: substance-specific coefficient) determined by the intensity of static magnetic field, energy moves to the side of atomic nuclei because of resonance, and the direction of magnetic vector changes (precession increases). When the oscillating magnetic field is turned off in this state, the precession gradually returns to the direction in the static magnetic field with the tilt angle returning to the previous angle. By externally detecting this process by an antenna coil, an NMR signal can be obtained.
The resonance frequency f0 mentioned above of hydrogen atom is 42.6×B0 (MHz) where B0 (T) represents the intensity of the static magnetic field.
Further, in nuclear magnetic resonance imaging, using changes appearing in detected signals in accordance with changes in the blood flow, it is possible to visualize an active portion of a brain activated in response to an external stimulus. Such a nuclear magnetic resonance imaging is specifically referred to as fMRI (functional MRI).
An fMRI uses a common MRI apparatus with additional hardware and software necessary for fMRI measurement.
The change in blood flow causes change in NMR signal intensity, since oxygenated hemoglobin has magnetic property different from that of deoxygenated hemoglobin. Hemoglobin is diamagnetic when oxygenated, and it does not have any influence on relaxation time of hydrogen atoms in the surrounding water. In contrast, hemoglobin is paramagnetic when deoxygenated, and it changes surrounding magnetic field. Therefore, when the brain receives any stimulus and local blood flow increases and oxygenated hemoglobin increases, the change can be detected by the MRI signals. The stimulus to a subject may include visual stimulus, audio stimulus, or performance of a prescribed task (see, for example, Non-Patent Literature 2).
In the studies of brain functions, brain activities are measured by measuring increase in nuclear magnetic resonance signal (MRI signal) of hydrogen atoms corresponding to a phenomenon that density of deoxygenated hemoglobin in red blood cells decrease in minute vein or capillary vessel (BOLD effect).
Particularly, in studies related to human motor function, brain activities are measured by the MRI apparatus as described above while a subject or subjects are performing some physical activity.
For human subjects, non-invasive measurement of brain functions is essential. In this aspect, decoding technique enabling extraction of more detailed information from fMRI data has been developed (see, for example, Non-Patent Literature 6). Specifically, pixel-by-pixel brain activity analysis (volumetric pixel: voxel) of brain by the fMRI enables estimation of stimulus input and state of recognition from spatial patterns of brain activity. The above-described DecNef is an application of such a decoding technique to a task related to sensory learning.